Roles of K+ and Cl- channels in cAMP-induced pulmonary vasodilation.
Increase in intracellular adenosine 3', 5'-cyclic monophosphate (cAMP) is a common pathway for many clinically used drugs to cause pulmonary artery (PA) relaxation. Activity of sarcolemmal K+ and Cl(-)-channels is an important determinant of membrane potential (Em), which, in turn, plays a critical role in regulating pulmonary vascular tone. Whether K+ and Cl- channels were involved in cAMP-induced PA relaxation was tested using isolated rat PA rings. Raising extracellular K+ concentration from 20 to 142.7 mM increased the K(+)-evoked contraction, but significantly decreased the relaxation induced by the adenylate cyclase activator, forskolin (FSK, 2.5 microM), suggesting that FSK-induced PA relaxation depended on transmembrane K+ gradient. Indeed, the FSK-induced relaxation was inhibited by 4-aminopyridine (4-AP, 10 mM), a voltage-gated K+ (Kv) channel blocker. Neither the Ca(2+)-activated K+ channel blocker, charybdotoxin, nor the ATP-sensitive K+ channel blocker, glibenclamide, had this effect. Furthermore, reducing extracellular Cl- concentration from 142.7 to 50 mM significantly decreased the FSK-induced relaxation in PA rings precontracted with 142.7 mM K+ (Ek approximately 0 mV), but negligibly affected the evoked contraction. This indicates that transmembrane Cl- gradient also regulates FSK-induced PA relaxation. Indeed, the Cl- channel blocker, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, 10 microM), significantly inhibited the FSK-induced relaxation in PA rings preconstricted by 142.7 mM K+. In summary, the data suggest that the cAMP-induced PA relaxation is attributable, at least partly, to both activation of the 4-AP-sensitive Kv channels and stimulation of the NPPB-sensitive Cl- channels.
Zhao
Y J
YJ
Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.
Wang
J
J
Rubin
L J
LJ
Yuan
X J
XJ
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D018118:Chloride Channels / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D018118:Chloride Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D005576:Colforsin; D000242:Cyclic AMP